New Candidate Vaccines against Blood-Stage Plasmodium falciparum Malaria: Prime-Boost Immunization Regimens Incorporating Human and Simian Adenoviral Vectors and Poxviral Vectors Expressing an Optimized Antigen Based on Merozoite Surface Protein 1

The Jenner Institute, University of Oxford, Oxford, United Kingdom.
Infection and immunity (Impact Factor: 3.73). 11/2010; 78(11):4601-12. DOI: 10.1128/IAI.00315-10
Source: PubMed


Although merozoite surface protein 1 (MSP-1) is a leading candidate vaccine antigen for blood-stage malaria, its efficacy
in clinical trials has been limited in part by antigenic polymorphism and potentially by the inability of protein-in-adjuvant
vaccines to induce strong cellular immunity. Here we report the design of novel vectored Plasmodium falciparum vaccines capable of overcoming such limitations. We optimized an antigenic insert comprising the four conserved blocks of
MSP-1 fused to tandemly arranged sequences that represent both allelic forms of the dimorphic 42-kDa C-terminal region. Inserts
were expressed by adenoviral and poxviral vectors and employed in heterologous prime-boost regimens. Simian adenoviral vectors
were used in an effort to circumvent preexisting immunity to human adenoviruses. In preclinical studies these vaccines induced
potent cellular immune responses and high-titer antibodies directed against MSP-1. The antibodies induced were found to have
growth-inhibitory activity against dimorphic allelic families of P. falciparum. These vectored vaccines should allow assessment in humans of the safety and efficacy of inducing strong cellular as well
as cross-strain humoral immunity to P. falciparum MSP-1.

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Available from: Leonie M van Duivenvoorde, Feb 25, 2014
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    • "Both the MSP1 and AMA1 viral vectored vaccines expressed bi-allelic constructs. In the case of MSP1 both major alleles of MSP119 were encoded [32], which differ by 4 amino acids – the ETSR allele (present in the 3D7 clone parasite used for CHMI studies) as well as the QKNG (or K1/Wellcome) allele. In the case of AMA1, two versions of the ectodomain were expressed [33] – the 3D7 and FVO alleles which differ by 24 amino acids. "
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    ABSTRACT: The development of protective vaccines against many difficult infectious pathogens will necessitate the induction of effective antibody responses. Here we assess humoral immune responses against two antigens from the blood-stage merozoite of the Plasmodium falciparum human malaria parasite - MSP1 and AMA1. These antigens were delivered to healthy malaria-naïve adult volunteers in Phase Ia clinical trials using recombinant replication-deficient viral vectors - ChAd63 to prime the immune response and MVA to boost. In subsequent Phase IIa clinical trials, immunized volunteers underwent controlled human malaria infection (CHMI) with P. falciparum to assess vaccine efficacy, whereby all but one volunteer developed low-density blood-stage parasitemia. Here we assess serum antibody responses against both the MSP1 and AMA1 antigens following i) ChAd63-MVA immunization, ii) immunization and CHMI, and iii) primary malaria exposure in the context of CHMI in unimmunized control volunteers. Responses were also assessed in a cohort of naturally-immune Kenyan adults to provide comparison with those induced by a lifetime of natural malaria exposure. Serum antibody responses against MSP1 and AMA1 were characterized in terms of i) total IgG responses before and after CHMI, ii) responses to allelic variants of MSP1 and AMA1, iii) functional growth inhibitory activity (GIA), iv) IgG avidity, and v) isotype responses (IgG1-4, IgA and IgM). These data provide the first in-depth assessment of the quality of adenovirus-MVA vaccine-induced antibody responses in humans, along with assessment of how these responses are modulated by subsequent low-density parasite exposure. Notable differences were observed in qualitative aspects of the human antibody responses against these malaria antigens depending on the means of their induction and/or exposure of the host to the malaria parasite. Given the continued clinical development of viral vectored vaccines for malaria and a range of other diseases targets, these data should help to guide further immuno-monitoring studies of vaccine-induced human antibody responses.
    PLoS ONE 09/2014; 9(9):e107903. DOI:10.1371/journal.pone.0107903 · 3.23 Impact Factor
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    • "Human adenovirus serotype 5 was chosen in this study as a model adenovirus due to lack of intellectual property restrictions and its induction of comparable immunogenicity in pre-clinical models to clinically-tested simian adenoviruses928. Our data from previous murine studies using a different transgene expressed from HAdV5 (and from human clinical trials with a related adenoviral malaria vaccine expressing the antigen METRAP7), demonstrated that parenteral administration of lower doses of adenovirus-based vaccines (ID in mouse, IM in human) induced lower immune responses to the transgene and to the adenovirus vector2628. Adenovirus-naïve animals were used to model immunization of individuals that would be naïve to simian or other rare human adenovirus-based vaccines that are being developed for clinical use. "
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    ABSTRACT: Substantial effort has been placed in developing efficacious recombinant attenuated adenovirus-based vaccines. However induction of immunity to the vector is a significant obstacle to its repeated use. Here we demonstrate that skin-based delivery of an adenovirus-based malaria vaccine, HAdV5-PyMSP142, to mice using silicon microneedles induces equivalent or enhanced antibody responses to the encoded antigen, however it results in decreased anti-vector responses, compared to intradermal delivery. Microneedle-mediated vaccine priming and resultant induction of low anti-vector antibody titres permitted repeated use of the same adenovirus vaccine vector. This resulted in significantly increased antigen-specific antibody responses in these mice compared to ID-treated mice. Boosting with a heterologous vaccine; MVA-PyMSP142 also resulted in significantly greater antibody responses in mice primed with HAdV5-PyMSP142 using MN compared to the ID route. The highest protection against blood-stage malaria challenge was observed when a heterologous route of immunization (MN/ID) was used. Therefore, microneedle-mediated immunization has potential to both overcome some of the logistic obstacles surrounding needle-and-syringe-based immunization as well as to facilitate the repeated use of the same adenovirus vaccine thereby potentially reducing manufacturing costs of multiple vaccines. This could have important benefits in the clinical ease of use of adenovirus-based immunization strategies.
    Scientific Reports 08/2014; 4. DOI:10.1038/srep06154 · 5.58 Impact Factor
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    • "To enable detection of antibodies from HAdV5 vectors, the TIP antigen was fused to EGFP, providing an additional H-2Kd restricted CD8+ T cell epitope HYLSTQSAL [59] (Proimmune). Responses to P. falciparum MSP-1 was measured against a pool containing H-2b defined CD4+ epitope M188 (DKIDLFKNPYDFEAIK) and a pool containing CD8+ T cell epitopes M86 (IPYKDLTSSNYVVKD), M100 (INDKQGENEKYLPFL) and M149 (YRSLKKQIEKNIFT) [60], P. falciparum AMA-1 with a pool of the dominant H-2d epitopes A31 (VFGKGIIIENSKTTF), A41 (FYKDNKYVKNLDELT), A42 (KYVKNLDELTLCSRH) and A95 (NKKIIAPRIFISDDK) [61], [62] and P. falciparum circumsporozoite protein (CS) with the dominant H-2Kd CD8+ T cell epitope CS39–47 (NYDNAGTNL) [63]. Responses to 4-1BBL were measured against a single pool containing 15 mer peptides (overlapping by 5) spanning the length of either mouse 4-1BBL (GenBank accession no. "
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    ABSTRACT: T cells play a central role in the immune response to many of the world's major infectious diseases. In this study we investigated the tumour necrosis factor receptor superfamily costimulatory molecule, 4-1BBL (CD137L, TNFSF9), for its ability to increase T cell immunogenicity induced by a variety of recombinant vectored vaccines. To efficiently test this hypothesis, we assessed a number of promoters and developed a stable bi-cistronic vector expressing both the antigen and adjuvant. Co-expression of 4-1BBL, together with our model antigen TIP, was shown to increase the frequency of murine antigen-specific IFN-γ secreting CD8+ T cells in three vector platforms examined. Enhancement of the response was not limited by co-expression with the antigen, as an increase in CD8+ immunogenicity was also observed by co-administration of two vectors each expressing only the antigen or adjuvant. However, when this regimen was tested in non-human primates using a clinical malaria vaccine candidate, no adjuvant effect of 4-1BBL was observed limiting its potential use as a single adjuvant for translation into a clinical vaccine.
    PLoS ONE 08/2014; 9(8):e105520. DOI:10.1371/journal.pone.0105520 · 3.23 Impact Factor
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